Tryptophan is an essential amino acid, serving as the precursor of the neurotransmitter, serotonin, and of the hormone, melatonin, in addition to its roles in enzymes and in receptor proteins. Tryptophan is metabolized in mammals by a pyrroloxygenase in the liver, where it can serve as a precursor of nicotinamide (Vitamin B6) in some animals. In other tissues, tryptophan and related indoles are metabolized by a distinct oxygenase, the activity of which is dramatically increased (up to 100-fold) upon administration of bacterial lipopolysaccharides or interferon. The role of this oxygenase in the response of the organism to infection is unknown, however. We anticipated that certain 2-substituted tryptophans might serve as selective "suicide substrates" for these oxygenases. Analogs of tryptophan with electronegative substitutents at C-2 had not been previously prepared. We have obtained 2-chloro- and 2-bromo-L-tryptophan by radical halogenation, and 2-nitro-L-tryptophan as a minor product of direct nitration. The mechanisms of hydrolysis of the 2-halotryptophans at low pH have now been fully elucidated and reveal the involvement of intramolecular proton transfer in the conversion of the stable indole to the labile indolenine tautomer. An enzyme carboxyl group should also promote indolenine formation, suggesting the indolenine to be the true substrate for tryptophan enzymes. Indeed 2-oxindoly1-L-alanine and 2,3-dihydrotryptophan are excellent competitive inhibitors of these enzymes. This unique catalytic power of the carboxyl is now being utilized to catalyze the replacement of the 2-halo group by other nucleophiles in aprotic solvents. The availability of the novel 2-nitrotryptophan now provides an alternative route to other 2-substituted tryptophans--of potential value as affinity and photoaffinity labels, and as antibacterial agents. 5-Azido-L-tryptophan has already been found effective as a photoaffinity label for tryptophan synthase. The properties and hydrolysis mechanisms of 2-haloindole-3-acetic acids contrast markedly with those of the analogous propionic acids.